title: Skeletal muscle-specific deletion of lipoprotein lipase enhances insulin signaling in skeletal muscle but causes insulin resistance in liver and other tissues.
abstract: OBJECTIVE
  Skeletal muscle-specific LPL knockout mouse (SMLPL(-/-)) were created to study the systemic impact of reduced lipoprotein lipid delivery in skeletal muscle on insulin sensitivity, body weight, and composition.
  
  
  METHODS
  Tissue-specific insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp and 2-deoxyglucose uptake. Gene expression and insulin-signaling molecules were compared in skeletal muscle and liver of SMLPL(-/-) and control mice.
  
  
  RESULTS
  Nine-week-old SMLPL(-/-) mice showed no differences in body weight, fat mass, or whole-body insulin sensitivity, but older SMLPL(-/-) mice had greater weight gain and whole-body insulin resistance. High-fat diet feeding accelerated the development of obesity. In young SMLPL(-/-) mice, insulin-stimulated glucose uptake was increased 58% in the skeletal muscle, but was reduced in white adipose tissue (WAT) and heart. Insulin action was also diminished in liver: 40% suppression of hepatic glucose production in SMLPL(-/-) vs. 90% in control mice. Skeletal muscle triglyceride was 38% lower, and insulin-stimulated phosphorylated Akt (Ser473) was twofold greater in SMLPL(-/-) mice without changes in IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase activity. Hepatic triglyceride and liver X receptor, carbohydrate response element-binding protein, and PEPCK mRNAs were unaffected in SMLPL(-/-) mice, but peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1alpha and interleukin-1beta mRNAs were higher, and stearoyl-coenzyme A desaturase-1 and PPARgamma mRNAs were reduced.
  
  
  CONCLUSIONS
  LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition. Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance.
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Knaub
authors.forename: Dalan R
authors.initials: DR
authors.lastname: Jensen
authors.forename: Dae
authors.initials: D
authors.lastname: Young Jung
authors.forename: Eun-Gyoung
authors.initials: EG
authors.lastname: Hong
authors.forename: Hwi-Jin
authors.initials: HJ
authors.lastname: Ko
authors.forename: Alison M
authors.initials: AM
authors.lastname: Coates
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: Becky A
authors.initials: BA
authors.lastname: de la Houssaye
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Janssen
authors.forename: Carrie E
authors.initials: CE
authors.lastname: McCurdy
authors.forename: Shaikh M
authors.initials: SM
authors.lastname: Rahman
authors.forename: Cheol
authors.initials: C
authors.lastname: Soo Choi
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
authors.forename: Robert H
authors.initials: RH
authors.lastname: Eckel
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D016207:Cytokines / Q000097:blood; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D012333:RNA, Messenger; D008071:Lipoprotein Lipase